US5851828A - Targeted cytolysis of HIV-infected cells by chimeric CD4 receptor-bearing cells - Google Patents

Targeted cytolysis of HIV-infected cells by chimeric CD4 receptor-bearing cells Download PDF

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US5851828A
US5851828A US08/284,391 US28439194A US5851828A US 5851828 A US5851828 A US 5851828A US 28439194 A US28439194 A US 28439194A US 5851828 A US5851828 A US 5851828A
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cells
cell
seq
hiv
receptor
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Brian Seed
Babak Banapour
Charles Romeo
Waldemar Kolanus
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General Hospital Corp
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General Hospital Corp
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Assigned to GENERAL HOSPITAL CORPORATION, THE reassignment GENERAL HOSPITAL CORPORATION, THE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KOLANUS, WALDEMAR, BANAPOUR, BABAK, ROMEO, CHARLES, SEED, BRIAN
Priority to SI9530722T priority patent/SI0750457T1/sl
Priority to KR1019960704450A priority patent/KR100289253B1/ko
Priority to PL95315908A priority patent/PL180066B1/pl
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Priority to PCT/US1995/000454 priority patent/WO1995021528A1/en
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Priority to KR1019970700681A priority patent/KR100384249B1/ko
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Priority to SI9530650T priority patent/SI0781095T1/xx
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Priority to PCT/US1995/009468 priority patent/WO1996003883A1/en
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Priority to AU32014/95A priority patent/AU697489B2/en
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Priority to CO95034525A priority patent/CO4410253A1/es
Priority to FI963150A priority patent/FI120264B/fi
Priority to NO19963379A priority patent/NO319378B1/no
Priority to MXPA/A/1996/003384A priority patent/MXPA96003384A/xx
Priority to NO19970440A priority patent/NO325081B1/no
Priority to FI970428A priority patent/FI119868B/fi
Priority to BR1100759-1A priority patent/BR1100759A/pt
Priority to HK98101624A priority patent/HK1002545A1/xx
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Publication of US5851828A publication Critical patent/US5851828A/en
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    • C12N2799/023—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a poxvirus

Definitions

  • HIV was shown to be the etiologic agent of AIDS. Since that time the definition of AIDS has been revised a number of times with regard to what criteria should be included in the diagnosis. However, despite the fluctuation in diagnostic parameters, the simple common denominator of AIDS is the infection with HIV and subsequent development of persistent constitutional symptoms and AIDS-defining diseases such as a secondary infections, neoplasms, and neurologic disease. Harrison's Principles of Internal Medicine, 12th ed., McGraw Hill (1991).
  • CD4 + T cells have been assigned the role of helper/inducer, indicating their function in providing an activating signal to B cells, or inducing T lymphocytes bearing the reciprocal CD8 marker to become cytotoxic/suppressor cells. Reinherz and Schlossman, Cell 19:821-827 (1980); Goldstein et al., Immunol. Rev. 68:5-42 (1982).
  • a 32 kDa type I integral membrane homodimer, ⁇ (zeta) has a 9 residue extracellular domain with no sites for N-linked glycan addition, and a 112 residue (mouse) or 113 residue (human) intracellular domain (Weissman et al., Science 238:1018-1020 (1988); Weissman et al., Proc. Natl. Acad. Sci. USA 85:9709-9713 (1988)).
  • An isoform of ⁇ called ⁇ (eta) (Baniyash et al., J. Biol. Chem. 263:9874-9878 (1988); Orloff et al., J. Biol. Chem.
  • the Fc receptor-associated ⁇ chain is expressed in cell surface complexes with additional polypeptides, some of which mediate ligand recognition, and others of which have undefined function.
  • ⁇ gamma
  • Fc ⁇ RI which consists of at least three distinct polypeptide chains (Blank et al., Nature 337:187-189 (1989); Ra et al., Nature 241:752-754 (1989)), and one of the low affinity receptors for IgG, represented in mice by Fc ⁇ RII ⁇ (Ra et al., J. Biol.
  • T cell receptor (TCR) ⁇ chain TCR ⁇ chain
  • Fc receptor ⁇ y chain interact with ligand recognition domains of different immune system receptors and can autonomously initiate cellular effector programs, including cytolysis, following aggregation (Samelson et al., Cell 43:223-231 (1985); Weissman et al., Science 239:1018-1020 (1988); Jin et al., Proc. Natl. Acad. Sci.
  • the invention features a method of directing a cellular immune response against an HIV-infected cell in a mammal.
  • the method involves administering to the mammal an effective amount of therapeutic cells, the therapeutic cells expressing a membrane-bound, proteinaceous chimeric receptor comprising (a) an extracellular portion which includes a fragment of CD4 which is capable of specifically recognizing and binding the HIV-infected cell but which does not mediate HIV infection and (b) an intracellular portion which is capable of signalling the therapeutic cell to destroy the receptor-bound HIV-infected cell.
  • the CD4 fragment is amino acids 1-394 of CD4 or is amino acids 1-200 of CD4; the CD4 fragment is separated from the intracellular portion by the CD7 transmembrane domain shown in FIG. 26 or by the hinge, CH2, and CH3 domains of the human IgG1 molecule shown in FIG.
  • the invention features DNA encoding a chimeric receptor of the invention; and a vector including that chimeric receptor DNA.
  • the most convenient method for delivery of the chimeras to immune system cells is through some form of genetic therapy.
  • reconstituting immune system cells with chimeric receptors by mixture of the cells with suitably solubilized purified chimeric protein would also result in the formation of an engineered cell population capable of responding to HIV-infected targets.
  • Similar approaches have been used, for example, to introduce the CD4 molecule into erythrocytes for therapeutic purposes. In this case the engineered cell population would not be capable of self renewal.
  • the present invention relates to functional and simplified chimeras between CD4 fragments and T cell receptor, B cell receptor, and Fc receptor subunits which are capable of directing immune cells to recognize and lyse HIV-infected cells.
  • the method for directing the cellular response in a mammal comprises administering an effective amount of therapeutic cells (for example, cytotoxic T lymphocytes) to the mammal, the cells being capable of recognizing and destroying the HIV-infected cell.
  • therapeutic cells for example, cytotoxic T lymphocytes
  • the invention also includes the chimeric receptor proteins which direct the cytotoxic T lymphocytes to recognize and lyse HIV-infected cells, the host cells transformed with a vector comprising the chimeric receptors, and antibodies directed against the chimeric receptors.
  • cDNA is meant complementary or copy DNA produced from an RNA template by the action of RNA-dependent DNA polymerase (reverse transcriptase).
  • a “cDNA clone” means a duplex DNA sequence complementary to an RNA molecule of interest, carried in a cloning vector.
  • substantially pure means a nucleic acid sequence, segment, or fragment that is not immediately contiguous with (i.e., covalently linked to) both of the coding sequences with which it is immediately contiguous (i.e., one at the 5' end and one at the 3' end) in the naturally occurring genome of the organism from which the DNA of the invention is derived.
  • a "fragment" of a molecule is meant to refer to any contiguous nucleotide subset of the molecule.
  • An “analog” of a molecule is meant to refer to a non-natural molecule substantially similar to either the entire molecule or a fragment thereof.
  • a molecule is said to be “substantially similar” to another molecule if the sequence of amino acids in both molecules is substantially the same. Substantially similar amino acid molecules will possess a similar biological activity.
  • a molecule is said to be a "chemical derivative" of another molecule when it contains chemical moieties not normally a part of the molecule.
  • Such moieties may improve the molecule's solubility, absorption, biological half life, etc.
  • the moieties may alternatively decrease the toxicity of the molecule, eliminate or attenuate any undesirable side effect of the molecule, etc.
  • Moieties capable of mediating such effects are disclosed, for example, in Remington's Pharmaceutical Sciences, 16th ed., Mack Publishing Co., Easton, Penn. (1980).
  • immunodeficiency virus is meant a retrovirus that, in wild-type form, is capable of infecting T4 cells of a primate host and possesses a viral morphogenesis and morphology characteristic of the lentivirus subfamily.
  • the term includes, without limitation, all variants of HIV and SIV, including HIV-1, HIV-2, SIVmac, SIVagm, SIVmnd, SIVsmm, SIVman, SIVmand, and SIVcpz.
  • FIG. 2 shows surface expression of CD16 TM following coinfection of CD16 TM alone (dense dots), or coinfected with virus expressing CD4: ⁇ (dashes) or CD4: ⁇ (solid line). Sparse dots, cells infected with CD4: ⁇ alone, stained with 3G8 (Fleit et al., Proc. Natl. Acad. Sci. USA 79:3275-3279 (1982)) (anti-CD16 MAb).
  • FIG. 3 shows surface expression of CD16 TM following coinfection by viruses expressing CD16 TM and the following ⁇ chimeras: CD4: ⁇ (thick line), CD4: ⁇ C11G (solid line); CD4: ⁇ (dashed line); CD4: ⁇ C11G/D15G (dense dots); no coinfection (CD16 TM alone, sparse dots).
  • Cells were incubated with anti-CD16 MAb 3G8 and phycoerythrin-conjugated Fab' 2 goat antibodies to mouse IgG.
  • the level of expression of the ⁇ chimeras was essentially identical for the different mutants analyzed, and coinfection of cells with viruses expressing CD16 TM and ⁇ chimeras did not appreciably alter surface expression of the chimeras.
  • FIG. 4A-D shows increased intracellular free calcium ion follows crosslinking of mutant ⁇ chimeras in a T cell line.
  • Jurkat E6 cells Weiss et al., J. Immunol. 133:123-128 (1984)
  • the results shown are for the gated CD4 + population, so that only cells expressing the relevant chimeric protein are analyzed.
  • the mean ratio of violet to blue Indo-1 fluorescence reflects the intracellular free calcium concentration in the population as a whole and the percentage of responding cells reflects the fraction of cells which exceed a predetermined threshold ratio (set so that 10% of untreated cells are positive).
  • FIGS. 4B show Jurkat cells expressing CD4: ⁇ (solid line) or CD16: ⁇ (dashed line) which were exposed to anti-CD4 MAb Leu3a (phycoerythrin conjugate), followed by crosslinking with goat antibody to mouse IgG. The dotted line shows the response of uninfected cells to anti-CD3 MAb OKT3.
  • FIGS. 4C and 4D show Jurkat cells expressing CD4: ⁇ D15G (solid line); CD4: ⁇ C11G/D15G (dashes); or CD4; ⁇ C11G (dots) which were treated and analyzed as in FIGS. 4A and 4B.
  • FIG. 5A-C shows that CD4: ⁇ , CD4: ⁇ , and CD4: ⁇ receptors allow cytolytic T lymphocytes (CTL) to kill targets expressing HIV-1 gp120/41.
  • FIG. 5A solid circles, CTL expressing CD4: ⁇ incubated with HeLa cells expressing gp120/41; open circles, CTL expressing CD4: ⁇ incubated with uninfected HeLa cells; solid squares, uninfected CTL incubated with HeLa cells expressing gp120/41; open squares, uninfected CTL incubated with uninfected HeLa cells.
  • FIG. 5A solid circles, CTL expressing CD4: ⁇ incubated with HeLa cells expressing gp120/41; open circles, CTL expressing CD4: ⁇ incubated with uninfected HeLa cells; solid squares, uninfected CTL incubated with HeLa cells expressing gp120/41; open squares, uninfected CTL incubated with uninf
  • the percent of cells expressing CD4 chimera was determined by subtracting the scaled negative (uninfected) population by histogram superposition; for comparative purposes in this figure the uninfected cells were assigned an arbitrary threshold which gives roughly the same fraction positive for the other cell populations as would histogram subtraction.
  • 6B solid circles, CTL expressing CD4: ⁇ incubated with Raji (MHC class II + ) cells; open circles, uninfected CTL cells incubated with RJ2.2.5 (MHC class II - Raji mutant) cells; solid squares, uninfected CTL incubated with Raji (MHC class II + ) cells; open squares, CTL expressing CD4: ⁇ incubated with RJ2.2.5 (MHC class II - ) cells.
  • the ordinate scale is expanded.
  • FIG. 7A-B shows characterization of the CD16: ⁇ chimeric receptor.
  • FIG. 7A is a schematic diagram of the CD16: ⁇ fusion protein. The extracellular portion of the phosphatidylinositol-linked form of monomeric CD16 was joined to dimeric ⁇ just external to the transmembrane domain. The protein sequence at the fusion junction is shown at the bottom (SEQ ID NOS: 42,43).
  • FIG. 7B shows a flow cytometric analysis of calcium mobilization following crosslinking of the CD16: ⁇ chimera in either a TCR positive or TCR negative cell line. The mean ratio of violet to blue fluorescence (a measure of relative calcium ion concentration) among cell populations treated with antibodies at time 0 is shown.
  • FIG. 10A-F shows the contribution of individual amino acids to the activity of the 18 residue cytolytic signal-transducing motif.
  • FIGS. 10A and 10B show cytolytic activity and FIG. 10C shows calcium ion mobilization mediated by chimeras bearing point mutations near the carboxyl terminal tyrosine (Y62).
  • FIGS. 10A and 10B represent data collected on cells expressing low and high amounts, respectively, of the CD16: ⁇ fusion proteins. Identical symbols are used for the calcium mobilization and cytolysis assays, and are shown in one letter code at right.
  • FIGS. 10D and 10E show cytolytic activity and FIG. 10F shows calcium ion mobilization by chimeras bearing point mutations near the amino terminal tyrosine (Y51). Identical symbols are used for the calcium mobilization and cytolysis assays and are shown at right.
  • FIG. 11A-B shows alignment of internal repeats of ⁇ and comparison of their ability to support cytolysis.
  • FIG. 11A is a schematic diagram of chimeras formed by dividing the ⁇ intracellular domain into thirds and appending them to the transmembrane domain of a CD16:7 chimera. The sequences of the intracellular domains are shown below (SEQ ID NOS: 48-50), with shared residues boxed, and related residues denoted by asterisks.
  • FIG. 11B shows the cytolytic potency of the three ⁇ subdomains.
  • Solid circles, cells expressing CD16: ⁇ (mfi 476); solid squares, CD16:7: ⁇ (33-65) (mfi 68); open squares, CD16:7: ⁇ (71-104) (mfi 114); and solid triangles, CD16:7: ⁇ (104-138) (mfi 104).
  • FIG. 16 shows the amino acid sequence of the CD3 delta receptor prein; the boxed sequence represents a preferred cytolytic signal transducing portion.
  • FIG. 20 shows a schematic diagram of the CD4 chimeras.
  • Molecule "A” is CD4(D1-D4):Ig:CD7;
  • molecule "B” is CD4(D1,D2):Ig:CD7;
  • molecule "C” is CD4(D1-D4):Ig:CD7: ⁇ ;
  • molecule "D” is CD4(D1,D2):Ig:CD7: ⁇ ;
  • molecule "E” is CD4: ⁇ .
  • the extracellular domain of the human CD4 molecule corresponding to amino acids 1-394 of the precursor was joined by a BamHI site to the hinge, CH1, and CH2 domains of human IgG1 as described previously (Zettlmeissl et al., DNA Cell Biol.
  • Cells were grown for at least 10 days before use in cytotoxicity assays. Cells were infected with the appropriate recombinant vaccinia viruses as described herein for vPE16. Infections were allowed to proceed for an additional 3-4 hours in complete medium after which cells were harvested by centrifugation and resuspended at a density of 1 ⁇ 10 7 /ml. 100 ⁇ l were added to each well of a U-bottom microtiter plate containing 100 ⁇ l per well of complete medium and diluted in 2-fold serial steps. Two wells for each sample did not contain lymphocytes, to allow spontaneous chromium release and total chromium uptake to be measured.
  • HeLa subline S3 HeLa-S3, ATCC
  • 10 6 infected cells were detached with PBS and 1 mM EDTA, centrifuged and resuspended in 100 ⁇ g of 51 Cr sodium chromate (1 mCi/ml in PBS) for 1 hour at 37° C. and then washed three times with PBS.
  • 100 ⁇ l of labelled target cells were added to each well.
  • the microtiter plate was spun at 750 ⁇ g for 1 minute and incubated for 4 hours at 37° C.
  • the cells in each well were resuspended by gentle pipetting, a sample removed to determine the total counts incorporated and the microtiter plate was spun at 750 ⁇ g for 1 min. Aliquots (100 ⁇ l) of the supernatant were removed and counted in a gamma ray scintillation counter. The effector:target ratio was corrected for the percent of cells infected as measured by flow cytometry.
  • FIG. 22 shows replication of HIV-1 in transfectant cell lines.
  • Cell lines stably expressing wild type CD4 and various recombinant chimeras were established in a subline of the human embryonal kidney cell line 293.
  • a virus stock of the HIV-1 IIIB isolate was prepared with a titer of ⁇ 10 6 infectious particles/ml as measured by end-point dilution analysis using the human T-cell line C8166 as an indicator. Infections were carried out at an approximate MOI of 1 for a period of 8-12 hours at 37° C.
  • the cells were washed with PBS three times, trypsinized, replated in new dishes and the culture supernatant sampled for p24 titer (designated day 0).
  • FIG. 23 shows the nucleic acid (SEQ ID NO: 28) and amino acid (SEQ ID NO: 29) sequence of the D1-D4 domains of CD4 (CD4 Bam).
  • FIG. 24 shows the nucleic acid (SEQ ID NO: 30) and amino acid (SEQ ID NO: 31) sequence of the D1-D2 domains of CD4 (CD4 Nhe).
  • FIG. 25 shows the nucleic acid (SEQ ID NO: 32) and amino acid (SEQ ID NO: 33) sequence of the hinge, CH2, and CH3 domains of human IgG1 (Igh23 Bam).
  • FIG. 26 shows the nucleic acid (SEQ ID NO: 34) and amino acid (SEQ ID NO: 35) sequence of the transmembrane domain of CD7 (TM7 Bam Mlu).
  • FIG. 27 shows the nucleic acid (SEQ ID NO: 36) and amino acid (SEQ ID NO: 37) sequence of the intracellular domain of zeta (Zeta Mlu Not).
  • FIG. 28 shows the DNA sequence (SEQ ID NO: 51) and primary amino acid sequence (SEQ ID NO: 51) of a synthetic alpha helix.
  • Human IgG1 heavy chain sequences were prepared by joining sequences in the C H 3 domain to a cDNA fragment derived from the 3' end of the transmembrane form of the antibody mRNA.
  • the 3' end fragment was obtained by polymerase chain reaction using a tonsil cDNA library as substrate, and oligonucleotides having the sequences:
  • the 5' oligo is complementary to a site in the C H 1 domain of human IgG1, and the 3' oligo is complementary to a site just 5' of the sequences encoding the membrane spanning domain.
  • the PCR product was digested with BstXI and BamHI and ligated between BstXI and BamHI sites of a semisynthetic IgG1 antibody gene bearing variable and constant regions.
  • the amplified portions of the construct were replaced up to the SmaI site in C H 3 by restriction fragment interchange, so that only the portion between the SmaI site and the 3' oligo was derived from the PCR reaction.
  • the heavy chain gene ending in a BamHI site was joined to the BamHI site of the ⁇ chimera described below, so that the antibody sequences formed the extracellular portion.
  • Flow cytometry of COS cells transfected with a plasmid encoding the chimera showed high level expression of antibody determinants when an expression plasmid encoding a light chain cDNA was cotransfected, and modest expression of antibody determinants when the light chain expression plasmid was absent.
  • T cell receptor or Fc receptor protein Similar chimeras including human IgG1 fused to ⁇ or ⁇ (see below), or any signal-transducing portion of a T cell receptor or Fc receptor protein may be constructed generally as described above using standard techniques of molecular biology.
  • the expression plasmid resulting from these manipulations consisted of the semisynthetic heavy chain gene, followed by the grp78 leader sequences, followed by the kappa light chain cDNA sequences, followed by polyadenylation signals derived from an SV40 DNA fragment. Transfection of COS cells with the expression plasmid gave markedly improved expression of heavy chain determinants, compared to transfection of plasmid encoding heavy chain determinants alone.
  • the upstream heavy chain sequences can be replaced by any chimeric heavy chain/ receptor gene described herein.
  • a BamHI site was engineered into the sequence at the same approximate location (FIG. 1; SEQ ID NO: 2 and 5).
  • the gene fusions were introduced into a vaccinia virus expression plasmid bearing the E. coli gpt gene as a selectable marker, and inserted into the genome of the vaccinia WR strain by homologous recombination and selection for growth in mycophenolic acid (Falkner et al., J. Virol. 62:1849-1854 (1988); Boyle et al., Gene 65:123-128 (1988)).
  • the molecular masses of the monomeric CD4: ⁇ and CD4: ⁇ fusion proteins and native CD4 were found to be 63, 55 and 53 kD respectively.
  • the larger masses of the fusion proteins are approximately consistent with the greater length of the intracellular portion, which exceeds that of native CD4 by 75 (CD4: ⁇ ) or 5 (CD4: ⁇ ) residues.
  • FIG. 4A-D shows the results of calcium flux experiments with cells infected with CD4: ⁇ and the Asp - and Cys - mutants of ⁇ . Crosslinking of the chimeras, reproducibly increased intracellular calcium. CD4: ⁇ and CD4: ⁇ similarly allowed accumulation intracellular calcium in infected cells. Jurkat cells express low levels of CD4 on the cell surface, however, crosslinking of the native CD4 in the presence or absence of CD16: ⁇ does not alter intracellular calcium levels (FIG. 4A-B).
  • coli gpt gene as a selectable marker and inserted into the genome of the vaccinia WR strain by homologous recombination and selection for growth in mycophenolic acid (Falkner and Moss, J. Virol. 62:1849 (1988); Boyle and Coupar, Gene 65:123 (1988)).
  • the cells were detached from the plates with PBS/1 mM EDTA and surface labeled with 0.2 mCi 125 I per 2 ⁇ 10 6 cells using lactoperoxidase and H 2 O 2 by the method of Clark and Einfeld (Leukocyte Typing II, pp 155-167, Springer-Verlag, N.Y., 1986).
  • the labeled cells were collected by centrifugation and lysed in 1% NP-40, 0.1% SDS, 0.15M NaCl, 0.05M Tris, pH 8.0, 5 mM MgCl 2 , 5 mM KCl, 0.2M iodoacetamide and 1 mM PMSF.
  • CD16 proteins were immunoprecipitated with antibody 3G8 (Fleit et al., supra, 1982; Medarex) and anti-mouse IgG agarose (Cappel, Durham, N.C.). Samples were electrophoresed through an 8% polyacrylamide/SDS gel under non-reducing conditions or through a 10% gel under reducing conditions. These immunoprecipitations confirmed that the CD16: ⁇ Cys11Gly/Asp15Gly chimera did not associate in disulfide-linked dimer structures.
  • the cytolytic activity of the mutant receptors was also tested.
  • the mutated chimera deleted to residue 65 (CD16: ⁇ Cys11Gly/Asp15Gly/Asp66*) was, depending on the conditions of assay, two to eight fold less active in the cytolysis assay than the comparable unmutated chimera (CD16: ⁇ Asp66*), which was usually within a factor of two of, or indistinguishable in activity from, CD16: ⁇ (FIG. 9B).
  • the reduction in activity of the mutant chimeras is comparable to the reduction seen with CD4 chimeras of similar structure (see above) and is most likely attributable to the lower efficiency of ⁇ monomers compared to dimers.
  • FIG. 10A-F shows that while a number of relatively conservative substitutions (i.e., replacing acidic residues with their cognate amides, or tyrosine with phenylalanine) which spanned residues 59 to 63 yielded moderate compromise of cytolytic efficacy, in general the variants retained the ability to mobilize calcium.
  • the intracellular domain of ⁇ was divided into three segments, spanning residues 33 to 65, 71 to 104, and 104 to 138. Each of these segments was attached to a CD16:CD7 chimera by means of a MluI site introduced just distal to the basic membrane anchoring sequences of the intracellular domain of CD7 (see below; FIG. 11A). Comparison of the cytolytic efficacy of the three elements showed they were essentially equipotent (FIG. 11B). Sequence comparison (FIG. 11A) shows that the second motif bears eleven residues between tyrosines, whereas the first and third motifs bear ten.
  • chimeras bearing the 18 residue motif are approximately eight-fold less active than chimeras based on full length ⁇ , the reduced activity can be attributed to the loss of transmembrane interactions which normally allow wild-type ⁇ to form disulfide linked dimers. That is, ⁇ deletion constructs which have the same carboxyl terminus as the motif and lack transmembrane Cys and Asp residues typically show slightly less activity than chimeras bearing only the 18 residue motif.
  • ⁇ is not phosphorylated in response to receptor stimulation (Bauer et al., supra, 1991).
  • the presence of all three motifs is required for phosphorylation, or the third motif represents a favored substrate for an unidentified tyrosine kinase.
  • the PCR fragments were inserted into vaccinia virus expression vectors which contained the CD16 or CD4 extracellular domains respectively and subsequently inserted into wild type vaccinia by recombination at the thymidine kinase locus, using selection for cointegration of E coli gpt to facilitate identification of the desired recombinants.
  • the identities of all isoforms (shown in FIG. 12) were confirmed by dideoxy sequencing.
  • JRT3.T3.5 Approximately 10 7 JRT3.T3.5 cells were infected for one hour in serum free IMDM medium with recombinant vaccinia at a multiplicity of infection of at least ten. Twelve hours post-infection, the cells were harvested and surface labeled with 0.5mCi 125 I per 10 7 cells using the lactoperoxidase/glucose oxidase method (Clark and Einfeld, supra). The labeled cells were collected by centrifugation and lysed 1% NP-40, 0.1 mM MgCl 2 , 5 mM KCl, 0.2M iodoacetamide and 1 mM PMSF.
  • the recombinant viruses were used to infect the TCR - mutant Jurkat cell line JRT3.T3.5 (as described herein) and cytoplasmic free calcium was measured in the cells (as described herein) following crosslinking of the receptor extracellular domains with monoclonal antibody 3G8 or Leu-3A (as described herein).
  • cytoplasmic free calcium was measured in the cells (as described herein) following crosslinking of the receptor extracellular domains with monoclonal antibody 3G8 or Leu-3A (as described herein).
  • the CD4, CD5 and CD16 hybrids of FcR ⁇ II A shared essentially equal capacity to promote the calcium response (FIG. 13A-B).
  • FIG. 14A shows that CTL armed with CD16:FcR ⁇ IIA and C, but not FcR ⁇ II B1 or B2, are capable of lysing target cells expressing cell surface anti-CD16 antibody.
  • cytolysis experiments were conducted in which the FcRII intracellular domains were attached to a CD4 extracellular domain.
  • the target cells were HeLa cells expressing HIV envelope gp120/41 proteins (specifically, HeLa cells infected with the vaccinia vector vPE16 (available from the National Institute of Allergy and Infections Disease AIDS Depository, Bethesda, Md.).
  • target cells expressing HIV envelope were susceptible to lysis by T cells expressing the CD4:FcR ⁇ II A chimera, but not FcR ⁇ II B1 or B2 (FIG. 14B).
  • the intracellular domains of FcR ⁇ II A and C share no appreciable sequence homology with any other protein, including the members of the extended FcR ⁇ /TCR ⁇ family.
  • sequence elements responsible for induction of cytolysis 5' and 3' deletions of the intracellular domain coding sequences (described below and shown in FIG. 15A) were prepared and were evaluated for efficacy in calcium mobilization and cytolysis assays (as described herein).
  • the transmembrane domain of FcR ⁇ II was replaced with the transmembrane domain of the unrelated CD7 antigen to eliminate the possible contribution of interactions mediated by the membrane-spanning domain.
  • a tripartite fusion protein was created by genetic apposition of the extracellular domain of CD4 (FIG. 23) to the hinge, second, and third constant domains of human IgG1 heavy chain (Zettlmeissl et al. DNA Cell Biol. 9:347 (1990)) (FIG. 25), which were joined in this case to a portion of the first transmembrane exon of human membrane-bound IgG1, followed by a portion of the human CD7 antigen consisting of the sequences between the sole Ig-like domain and the stop transfer sequence following the transmembrane domain (Aruffo and Seed, EMBO J. 6:3313 (1987)) (FIG. 26).
  • the primary amino acid sequence of the extracellular moiety of the CD7 segment consisted of a proline-rich region suggestive of a stalk-like structure which projects the Ig-like domain away from the cell surface (Aruffo and Seed EMBO J. 6:3313 (1987)) (FIG. 26).
  • Recombinant vaccinia viruses were prepared to express this and related chimeras as described herein.
  • recombinant vaccinia viruses were generated by homologous recombination in CV-1 cells. At least two rounds of plaque visualization with OKT4 or Leu3a followed by plaque purification was performed for each stock prior to preparation of high titer stocks in CV-1 cells.
  • FIG. 21 shows that the intracellular domain of ⁇ fused to either CD4(D1-D4):Ig:CD7 or CD4(D1,D2):Ig:CD7 can confer killing ability; constructs lacking the ⁇ chain were not able to mediate this activity.
  • CD4: ⁇ a positive control, mediate a slightly more effective cytotoxicity
  • CD4(D1,D2):Ig:CD7: ⁇ a somewhat less effective cytotoxicity than CD4(D1-D4):Ig:CD7: ⁇ (FIG. 21).
  • Cells were metabolically labelled with 200 ⁇ Ci/ml of Tran 35 S-Label (ICN Radiochemicals, Irvine, Calif.) for 6-8 hours in cysteine and methioninedeficient medium and detached with PBS containing 1 mM EDTA. Cells were subsequently pelleted and lysed in 150 mM NaCl, 50 mM Tris pH 7.5, 5 mM EDTA, 0.5% NP-40, 0.1% SDS, 5 mM EDTA, 1 mM PMSF. Following the removal of the nuclei by centrifugation, one fifth of each cell extract was adsorbed onto washed protein A-conjugated agarose beads for 2 hours at 4° C.
  • Tran 35 S-Label ICN Radiochemicals, Irvine, Calif.
  • CD4 surface epitope density was significantly reduced in infected cultures expressing CD4, consistent with viral down-modulation, but was unaffected in cultures expressing CD4(D1-D4):Ig:CD7 and CD4(D1,D2):Ig:CD7.
  • CD4 represents CD4(D1-D4) unless otherwise noted;
  • H represents the hinge, CH2, and CH3 regions of the human IgG1 heavy chain, respectively;
  • CD7tm and stk represents the CD7 transmembrane and stalk regions;
  • CD7tm (long version) and “CD7tm (short version)” represent respectively the CD7 transmembrane region and the CD7 transmembrane region deleted for the proline-rich domain (as discussed above);
  • CD5tm represents the CD5 transmembrane region; and
  • CD34tm represents the CD34 transmembrane region.
  • Syncytia formation was scored in co-cultivation assays with HeLa cells expressing the HIV-1 envelope glycoprotein from the vaccinia virus vPE-16 construct (see above).
  • Thy-1 expression was measured as follows.
  • a live retrovirus vector was constructed based on the hxb.2 clone of HIV-1.
  • the non-essential nef gene was replaced with the coding sequence of rat thy-1, an efficiently expressed cell surface molecule that is anchored to the membrane by a phosphatidyl-inositol linkage.
  • the virus derived from this molecular clone, designated hxb/thy-1 was infectious as evidenced by its cytopathological effects and by the production of p24 in culture supernatants of infected C8166 cells (a human CD4 + leukemic T-cell line).
  • HeLa cells transiently transfected with CD4 showed signs of thy-1 expression in as early as 18 hours post-infection, as would be expected of a message regulated in a nef-like manner.
  • Messages encoded by the nef gene normally fall into a class of viral regulatory proteins which are multiply spliced and lack the rev-response element. These messages can accumulate constitutively in the cytoplasm as early viral gene products.
  • the thy-1 messages were expected to be similarly regulated, that is, to occur early in the life cycle of the virus. In short, this system facilitated the assay of HIV entry, with thy-1 expression employed as a surrogate for viral entry.
  • T cell receptor proteins CD3 delta and T3 gamma
  • B cell receptor proteins mb1 and B29.
  • the amino acid sequences of these proteins are shown in FIG. 16 (CD3 delta; SEQ ID NO: 24), FIG. 17 (T3 gamma; SEQ ID NO: 25), FIG. 18 (md1 ; SEQ ID NO: 26) and FIG. 19 (B29; SEQ ID NO: 27).
  • the portions of the sequences sufficient for cytolytic signal transduction (and therefore preferably included in a chimeric receptor of the invention) are shown in brackets. Chimeric receptors which include these protein domains are constructed and used in the therapeutic methods of the invention generally as described above.
  • CV1 cells were infected for one hour in serum free DME medium with recombinant vaccinia at a multiplicity of infection (moi) of at least ten (titer measured on CV1 cells).
  • the cells were placed in fresh medium after infection and labelled metabolically with 200 ⁇ Ci/ml 35 S-methionine plus cysteine (Tran 35 S-label, ICN; Costo Mesa, Calif.) in methionine and cysteine free DMEM (Gibco; Grand Island, N.Y.) for six hours.
  • the labelled cells were detached with PBS containing 1 mM EDTA, collected by centrifugation, and lysed in 1% NP-40, 0.1% SDS, 0.15M NaCl, 0.05M Tris pH 8.0, 5 mM EDTA, and 1 mM PMSF. Nuclei were removed by centrifugation, and CD4 proteins immunoprecipitated with OKT4 antibody and anti-mouse IgG agarose (Cappel, Durham, N.C.). Samples were electrophoresed through 8% polyacrylamide/SDS gels under non-reducing (NR) and reducing (R) conditions. Gels containing 35 S-labelled samples were impregnated with En 3 Hance (New England Nuclear, Boston, Mass.) prior to autoradiography.
  • CD16 TM transmembrane form of CD16
  • CV1 cells singly infected with CD16 TM
  • expression in cells coinfected with viruses encoding CD16 TM and ⁇ or ⁇ chimeras After infection and incubation for six hours or more, cells were detached from plates with PBS, 1 mM EDTA and the expression of CD16TM or the chimeras was measured by indirect immunofluorescence and flow cytometry.
  • Jurkat subline E6 (Weiss et al., J. Immunol. 133:123-128 (1984)) cells were infected with recombinant vaccinia viruses for one hour in serum free IMDM at an moi of 10 and incubated for three to nine hours in IMDM, 10% FBS. Cells were collected by centrifugation and resuspended at 3 ⁇ 10 6 cells/ml in complete medium containing 1 mM Indo-1 acetomethoxyester (Grynkiewicz et al., J. Biol. Chem. 260:3340-3450 (1985)) (Molecular Probes) and incubated at 37° C. for 45 minutes.
  • PE-conjugated Leu-3A (anti-CD4) (Becton Dickinson, Lincoln Park, N.J.) at 1 ⁇ g/ml was added to the cell suspension followed by 10 ⁇ g/ml of unconjugated goat anti-mouse IgG at time 0 or unconjugated 3G8 (anti-CD16) monoclonal antibody was added to the cell suspension at 1 ⁇ g/ml followed by 10 ⁇ g/ml of PE-conjugated Fab 2 ' goat anti-monse IgG at time 0. Histograms of the violet/blue emission ratio were collected from the PE positive (infected) cell population, which typically represented 40-80% of all cells.
  • the T cell antigen receptor response in uninfected cells was triggered by antibody OKT3, without crosslinking.
  • samples showing baseline drift toward lower intracellular calcium (without antibody) were excluded from the analysis.
  • Histogram data were subsequently analyzed by conversion of the binary data to ASCII using Write Hand Man (Cooper City, Fla.) software, followed by analysis with a collection of FORTRAN programs.
  • the violet/blue emission ratio prior to the addition of the second antibody reagents was used to establish the normalized initial ratio, set equal to unity, and the resting threshold ratio, set so that 10% of the resting population would exceed threshold.
  • Human T cell line WH3, a CD8 + CD4 - HLA B44 restricted cytolytic line was maintained in IMDM, 10% human serum with 100 U/ml of IL-2 and was periodically stimulated either nonspecifically with irradiated (3000 rad) HLA-unmatched peripheral blood lymphocytes and 1 ⁇ g/ml of phytohemagglutinin, or specifically, with irradiated B44-bearing mononuclear cells. After one day of nonspecific stimulation, the PHA was diluted to 0.5 ⁇ g/ml by addition of fresh medium, and after three days the medium was changed. Cells were grown for at least 10 days following stimulation before use in cytotoxicity assays.
  • the cells were infected with recombinant vaccinia at a multiplicity of infection of at least 10 for one hour in serum free medium, followed by incubation in complete medium for three hours. Cells were harvested by centrifugation and resuspended at a density of 1 ⁇ 10 7 cells/ml. 100 ⁇ l were added to each well of a U-bottom microtiter plate containing 100 ⁇ l/well of complete medium. Cells were diluted in two-fold serial steps. Two wells for each sample did not contain lymphocytes, to allow spontaneous chromium release and total chromium uptake to be measured.
  • the target cells from HeLa subline S3, were infected in 6.0 or 10.0 cm plates at an approximate moi of 10 for one hour in serum free medium, followed by incubation in complete medium for three hours. They were then detached from the dishes with PBS, 1 mM EDTA and counted. An aliquot of 10 6 target cells (HeLa, Raji, or RJ2.2.5 cells for the CD4 chimeric receptor experiments and 3G8 10-2 cells; Shen et al., Mol. Immunol.
  • the cells in each well were resuspended by gentle pipetting, a sample removed to determine the total counts incorporated, and the microtiter plate spun at 750 ⁇ g for 1 minute. 100 ⁇ l aliquots of supernatant were removed and counted in a gamma ray scintillation counter. The percent killing was corrected for the fraction of infected target cells (usually 50-90%) measured by flow cytometry. For infected effector cells the effector:target ratio was corrected for the percent of cells infected (usually 20-50% for the CD4 chimeric receptor experiments and >70% for the CD16 chimeric receptor experiments).
  • synthetic oligonucleotide primers extending from the BamHI site upstream of the ⁇ transmembrane domain, and converting native ⁇ residue 11 from Cys to Gly (C11G) or residue 15 from Asp to Gly (D15G) or both (C11G/D15G) were prepared and used in PCR reactions to generate mutated fragments which were reinserted into the wild type CD4: ⁇ constructs.
  • ⁇ cDNA sequences were amplified by PCR using synthetic oligonucleotide primers designed to create a stop codon (UAG) after residues 50, 59, or 65.
  • the primers contained the cleavage site for the enzyme NotI indented five or six residues from the 5' end, usually in a sequence of the form CGC GGG CGG CCG CTA (SEQ ID NO: 11), where the last three residues correspond to the stop anticodon.
  • the NotI and stop anticodon sequences were followed by 18 or more residues complementary to the desired 3' end of the fragment.
  • the resulting chimeras were designated CD16: ⁇ Y51*, CD16: ⁇ E60* and CD16: ⁇ D66* respectively.
  • the ⁇ cDNA sequence corresponding to the transmembrane domain and the 17 following residues of the cytoplasmic domain was replaced by corresponding transmembrane and cytoplasmic domain obtained from the CD5 and CD7 cDNA.
  • the CD5 and CD7 fragments were generated by a PCR reaction using forward oligonucleotides including a BamHI restriction cleavage site and corresponding to the region just upstream of the transmembrane domain of CD5 and CD7 respectively and the following reverse oligonucleotides overlapping the CD5 and CD7 sequences respectively and the ⁇ sequence which contained the SacI restriction cleavage site.
  • CD5 ⁇ : CGC GGG CTC GTT ATA GAG CTG GTT CTG GCG CTG CTT CTT CTG (SEQ ID NO: 12)
  • CD7 ⁇ : CGC GGG GAG CTC GTT ATA GAG CTG GTT TGC CGC CGA ATT CTT ATC CCG (SEQ ID NO: 13).
  • ⁇ 104 CGC GGG ACG CGT ATT GGG ATG AAA GGC GAG CGC (SEQ ID NO: 17).
  • ⁇ , ⁇ , or ⁇ chimeras suffices to initiate the cytolytic effector cell response in T cells.
  • the known range of expression of ⁇ , ⁇ , and ⁇ which includes T lymphocytes, natural killer cells, basophilic granulocytes, macrophages and mast cells, suggests that conserved sequence motifs may interact with a sensory apparatus common to cells of hematopoietic origin and that an important component of host defense in the immune system may be mediated by receptor aggregation events.
  • the potency of the cytolytic response and the absence of a response to target cells bearing MHC class II receptors demonstrates that chimeras based on ⁇ , ⁇ , or ⁇ form the basis for a genetic intervention for AIDS through adoptive immunotherapy.
  • the broad distribution of endogenous ⁇ and ⁇ and evidence that Fc receptors associated with ⁇ mediate cytotoxicity in different cells types allows a variety of cells to be considered for this purpose. For example, neutrophilic granulocytes, which have a very short lifespan ( ⁇ 4h) in circulation and are intensely cytolytic, are attractive target cells for expression of the chimeras.
  • HIV recognition by cells expressing CD4 chimeras should also provide mitogenic stimuli, allowing the possibility that the armed cell population could respond dynamically to the viral burden.
  • expression of the chimeras in helper lymphocytes might provide an HIV-mobilized source of cytokines which could counteract the collapse of the helper cell subset in AIDS.
  • the ability to transmit signals to T lymphocytes through autonomous chimeras also provides the ability for the regulation of retrovirally engineered lymphocytes in vivo.
  • Crosslinking stimuli mediated for example by specific IgM antibodies engineered to remove complement-binding domains, may allow such lymphocytes to increase in number in situ, while treatment with similar specific IgG antibodies (for example recognizing an amino acid variation engineered into the chimeric chain) could selectively deplete the engineered population.
  • anti-CD4 IgM antibodies do not require additional crosslinking to mobilize calcium in Jurkat cells expressing CD4: ⁇ chimeras.
  • the ability to regulate cell populations without recourse to repeated extracorporeal amplification may substantially extend the range and efficacy of current uses proposed for genetically engineered T cells.

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US08/284,391 1991-03-07 1994-08-02 Targeted cytolysis of HIV-infected cells by chimeric CD4 receptor-bearing cells Expired - Lifetime US5851828A (en)

Priority Applications (54)

Application Number Priority Date Filing Date Title
US08/284,391 US5851828A (en) 1991-03-07 1994-08-02 Targeted cytolysis of HIV-infected cells by chimeric CD4 receptor-bearing cells
SI9530722T SI0750457T1 (sl) 1994-02-14 1995-01-12 Tarcna citoliza celic, inficiranih s HIV, s himernimi celicami, ki nosijo CD4 receptor
KR1019960704450A KR100289253B1 (ko) 1994-02-14 1995-01-12 키메라cd4수용체-포함세포에의한hiv감염세포의표적화세포용해
PL95315908A PL180066B1 (pl) 1994-02-14 1995-01-12 Bialkowy chimeryczny receptor blonowy, zmodyfikowana komórka,DNA kodujacy bialkowy chimeryczny receptor blonowy i wektor zawierajacy taki DNA PL PL PL PL PL PL PL
BR9506783A BR9506783A (pt) 1994-02-14 1995-01-12 Citólise alvejada de células infectadas por hiv por células portadoras de receptor de cd4 quimérico
AT95907414T ATE308888T1 (de) 1994-02-14 1995-01-12 Gezielte zell-lyse von hiv-infizierten zellen mit chimären cd4 rezeptortragenden zellen
DE69534589T DE69534589T2 (de) 1994-02-14 1995-01-12 Gezielte zell-lyse von hiv-infizierten zellen mit chimären cd4 rezeptortragenden zellen
NZ279123A NZ279123A (en) 1994-02-14 1995-01-12 Targeting immune response against hiv infected cells using chimeric cd4 receptor bearing cells
CA002182890A CA2182890C (en) 1994-02-14 1995-01-12 Targeted cytolysis of hiv-infected cells by chimeric cd4 receptor-bearing cells
AU15653/95A AU690204B2 (en) 1994-02-14 1995-01-12 Targeted cytolysis of HIV-infected cells by chimeric CD4 receptor-bearing cells
EP95907414A EP0750457B1 (en) 1994-02-14 1995-01-12 Targeted cytolysis of hiv-infected cells by chimeric cd4 receptor-bearing cells
UA96093460A UA42760C2 (uk) 1994-02-14 1995-01-12 Спосіб спрямування клітинної імунної відповіді проти віл-інфікованої клітини ссавця,білковий мембранозв'язаний химерний рецептор,днк,яка кодує химерний рецептор,вектор,що її містить
PCT/US1995/000454 WO1995021528A1 (en) 1994-02-14 1995-01-12 Targeted cytolysis of hiv-infected cells by chimeric cd4 receptor-bearing cells
JP52121395A JP3832850B2 (ja) 1994-02-14 1995-01-12 キメラｃｄ４レセプターを有する細胞によるｈｉｖ感染細胞を標的とする細胞傷害
DK95907414T DK0750457T3 (da) 1994-02-14 1995-01-12 Målrettet cytolyse af HIV-inficerede celler ved hjælp af kimær CD4-receptor-bærende celler
HU9602182A HU220100B (hu) 1994-02-14 1995-01-12 HIV-fertőzött sejtekkel szembeni sejtszintű immunválasz kiváltására képes kimérareceptort expresszáló terápiás sejtek és alkalmazásuk
ES95907414T ES2249766T3 (es) 1994-02-14 1995-01-12 Citolisis dirigida de celulas infectadas por hiv mediante celulas quimericas portadoras del receptor cd4.
CZ19962331A CZ293969B6 (cs) 1994-02-14 1995-01-12 Buňka nesoucí chimérický CD4 receptor, která ničí HIV infikované buňky a farmaceutický prostředek
CNB951925598A CN1318576C (zh) 1994-02-14 1995-01-12 由携载嵌合cd4受体的细胞针对hiv感染细胞的细胞溶解作用
IL112390A IL112390A (en) 1994-02-14 1995-01-19 The cell that expresses chimeric receptors, DNA vectors encoding the said receptors and pharmaceutical preparations containing them
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AT95928152T ATE234011T1 (de) 1994-08-02 1995-07-26 Zellen, die einen cd4-scheinrezeptor tragen und entsprechende moleküle und verfahren
SI9530650T SI0781095T1 (en) 1994-08-02 1995-07-26 Cells bearing cd4 decoy receptors and related molecules and methods
PL95318443A PL181085B1 (pl) 1994-08-02 1995-07-26 Środek do leczenia, komórka, białkopodobny chimeryczny receptor błonowy
CNB951951831A CN1142941C (zh) 1994-08-02 1995-07-26 带cd4引诱物受体的细胞以及相关分子和方法
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CA2195653A CA2195653C (en) 1994-08-02 1995-07-26 Cells bearing cd4 decoy receptors and related molecules and methods
PCT/US1995/009468 WO1996003883A1 (en) 1994-08-02 1995-07-26 Cells bearing cd4 decoy receptors and related molecules and methods
DK95928152T DK0781095T3 (da) 1994-08-02 1995-07-26 Celler der bærer CD4 lokkeduereceptorer og beslægtede molekyler og fremgangsmåder
AU32014/95A AU697489B2 (en) 1994-08-02 1995-07-26 Cells bearing cd4 decoy receptors and related molecules and methods
DE69529910T DE69529910T2 (de) 1994-08-02 1995-07-26 Zellen, die einen cd4-scheinrezeptor tragen und entsprechende moleküle und verfahren
IL114778A IL114778A (en) 1994-08-02 1995-07-30 Chemical cells carrying CD 4 receptors, membrane-bound receptors and the DNA encoding them
ZA956451A ZA956451B (en) 1994-08-02 1995-08-02 Cells bearing cd4 decoy receptors and related molecules and methods
CO95034525A CO4410253A1 (es) 1994-08-02 1995-08-02 Citolisis dirigida de celulas infectadas de hiv mediante celulas que portan el receptor cd4 quimerico
FI963150A FI120264B (fi) 1994-02-14 1996-08-12 Membraaniin sitoutunut kimeerinen respetoriproteiini
NO19963379A NO319378B1 (no) 1994-02-14 1996-08-13 DNA som koder for en kimaer reseptor, vektor og celle omfattende nevnte DNA, samt anvendelse av cellene.
MXPA/A/1996/003384A MXPA96003384A (es) 1994-02-14 1996-08-14 Citolisis objetivada de celulas infectadas por hiv mediante celulas portadoras receptoras cd4 quimericas
NO19970440A NO325081B1 (no) 1994-08-02 1997-01-31 Anvendelse av terapeutiske celler som inkluderer et fragment av CD4 for fremstilling av en farmasoytisk sammensetning for behandling av HIV.
FI970428A FI119868B (fi) 1994-08-02 1997-01-31 CD4-houkutusreseptoreita ilmentävien solujen käyttö
BR1100759-1A BR1100759A (pt) 1994-08-02 1997-05-12 Citólise alvejada de células infectadas por hiv por células portadoras de receptor de cd4 quimérico
HK98101624A HK1002545A1 (en) 1994-08-02 1998-03-03 Cells bearing cd4 decoy receptors and related molecules and methods
US09/218,950 US6284240B1 (en) 1991-03-07 1998-12-22 Targeted cytolysis of HIV-infected cells by chimeric CD4 receptor-bearing cells
US09/939,537 US7094599B2 (en) 1991-03-07 2001-08-24 Targeted cytolysis of HIV-infected cells by chimeric CD4 receptor-bearing cells

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US7094599B2 (en) 2006-08-22
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FI963150A (fi) 1996-10-10
EP0750457A1 (en) 1997-01-02
HU9602182D0 (en) 1996-10-28
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UA42760C2 (uk) 2001-11-15
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